Wu Lingyun, Shi Wenhui, Li Xiao, Chang Chunkang, Xu Feng, He Qi, Wu Dong, Su Jiying, Zhou Liyu, Song Luxi, Xiao Chao, Zhang Zheng
Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
J Transl Med. 2016 Mar 5;14:66. doi: 10.1186/s12967-016-0817-9.
Despite the efficacy of decitabine treatment in myelodysplastic syndrome (MDS), no definite predictor of response is known. In this study, we investigated whether the expression levels of human equilibrative nucleoside transporter 1 (hENT1), hENT2, deoxycytidine kinase (DCK) and cytidine deaminase (CDA) genes could predict response to decitabine in MDS.
We performed quantitative real-time PCR in marrow mononuclear cells to examine the expression of hENT1, hENT2, DCK, and CDA prior to therapy in 98 MDS patients initially treated with decitabine. Response and overall survival of patients treated with decitabine were analyzed according to gene expression levels. HENT1 knockdown was performed by shRNA in the SKM-1 cell line, and the effect of this on the demethylation ability of decitabine on long interspersed nucleotide element 1 (LINE1) was investigated.
Patients responding to decitabine presented with significantly higher hENT1 expression levels than non-responders (p = 0.004). Overall response, complete response, and cytogenetic complete response rate in patients with high hENT1 expression (79.4, 41.3, and 43.8 %) were significantly higher than those in patients with low hENT1 expression (48.6, 20.0, and 5.9 %, respectively) (p = 0.004, 0.033, and 0.006, respectively). In higher-risk MDS, patients with high hENT1 expression showed prolonged survival compared with those with low hENT1 expression (22.0 vs 14.0 months; p = 0.027). However, the expression levels of hENT2, DCK, and CDA did not affect response rate. Knockdown of hENT1 in SKM-1 cells weakened the demethylation effect on LINE1 induced by decitabine.
High expression of hENT1 appears to predict a good response to decitabine and a prolonged survival in higher-risk MDS patients treated with decitabine. HENT1 expression knockdown weakens the demethylation effect of decitabine.
尽管地西他滨治疗骨髓增生异常综合征（MDS）有效，但尚无明确的疗效预测指标。在本研究中，我们调查了人类平衡核苷转运体1（hENT1）、hENT2、脱氧胞苷激酶（DCK）和胞苷脱氨酶（CDA）基因的表达水平是否可预测MDS患者对地西他滨的反应。
我们对98例初始接受地西他滨治疗的MDS患者的骨髓单个核细胞进行定量实时PCR，以检测治疗前hENT1、hENT2、DCK和CDA的表达。根据基因表达水平分析接受地西他滨治疗患者的反应和总生存期。在SKM-1细胞系中通过短发夹RNA（shRNA）敲低HENT1，并研究其对 地西他滨对长散在核苷酸元件1（LINE1）的去甲基化能力的影响。
对地西他滨有反应的患者的hENT1表达水平显著高于无反应者（p = 0.004）。hENT1高表达患者的总反应率、完全缓解率和细胞遗传学完全缓解率（分别为79.4%、41.3%和43.8%）显著高于hENT1低表达患者（分别为48.6%、20.0%和5.9%）（p分别为0.004、0.033和0.006）。在高危MDS中，hENT1高表达患者的生存期比hENT1低表达患者延长（22.0个月对14.0个月；p = 0.027）。然而，hENT2、DCK和CDA的表达水平不影响反应率。SKM-1细胞中HENT1的敲低减弱了地西他滨对LINE1的去甲基化作用。
hENT1高表达似乎可预测地西他滨治疗高危MDS患者有良好反应及生存期延长。HENT1表达敲低减弱了地西他滨的去甲基化作用。
